In the hemocatharsis for therapy of renal failure, etc., modules such as hemodialyzers, hemofilters and hemodiafilters, which comprise dialysis membrans or ultrafilter membranes as separators are widely used in order to remove urinal toxic substances and waste products in blood. Dialysis membranes and ultrafilter membranes as separators are made up of natural materials such as cellulose or the derivatives thereof (e.g., cellulose diacetate, cellulose triacetate, etc.) or synthetic polymers such as polyslufone, polymethyl methacrylate, polyacrylonitrile, etc. The importance of modules comprising the hollow fiber membranes as separators is very high in the field of dialyzers, in view of the advantages such as the reduction of the amount of extracorporeal circulated blood, high efficiency of removing undesired substances in blood, and high productivity of manufacturing modules.
Highly water permeable polysulfone type resins have attracted public attentions, because such resins are most suitable for the advanced dialysis technology, among the above-listed membrane materials. However, semipermeable membranes made up of a polysulfone resin alone are poor in affinity with blood, inducing airlock phenomena, since the polysulfone type resin is hydrophobic. Therefore, such semipermeable membranes as they are can not be directly used for treating blood.
To solve this problem, there is proposed a method for imparting hydrophilicity to a membrane by blending a polysulfone type resin with a hydrophilic polymer: for example, a polyhydric alcohol such as polyethylene glycol or the like is added to a polysulfone type resin (cf. JP-A-61-232860 and JP-A-58-114702); or otherwise, polyvinyl pyrrolidone is added to a polysulfone type resin (cf. JP-B-5-54373 and JP-B-6-75667).
These methods are effective to solve the foregoing problem. However, finding of the optimum conditions for the hydrophilicity-imparting technique by blending a hydrophilic polymer is very important, because the concentration of the hydrophilic polymer in the inner surface of a hollow fiber membrane on the blood-contacting side and the concentration of the hydrophilic polymer in the outer surface thereof give significant influence on the capacities of the hollow fiber membrane. For example, the compatibility of a hollow fiber membrane with blood can be ensured by increasing the concentration of a hydrophilic polymer in the inner surface of the membrane, while too high a concentration of the hydrophilic polymer in the inner surface of the membrane increases the amount of the hydrophilic polymer eluted into blood. Undesirably, the accumulation of the eluted hydrophilic polymer induces side effects or complications over a long period of dialysis therapy.
On the other hand, too high a concentration of the hydrophilic polymer in the outer surface of the membrane induces a danger of the invasion of highly hydrophilic endotoxin in a dialyzate into the blood side. As a result, side effects such as fever, etc. are induced, or the hydrophilic polymer in the outer surfaces of the hollow fiber membranes permits the sticking of such membranes to one another while the membranes are being dried, which results in a new problem that the incorporation of such membranes into a module becomes hard.
On the contrary, a lower concentration of the hydrophilic polymer in the outer surface of the hollow fiber membrane is preferable, since the invasion of endotoxin into the blood side can be suppressed. However, the hydrophilicity of the outer surface of the hollow fiber membrane becomes lower, which causes a problem in that the outer surface of the hollow fiber membrane becomes poor in compatibility with physiological saline for use in wetting the membrane, when a bundle of dried hollow fiber membranes is wetted and incorporated into a module. As a result, undesirably, the priming of the membranes (purging the membranes of an air when wetting the same) may become lower in efficiency.
There is disclosed a method for solving these problems (cf. JP-A-6-165926): that is, the concentration of a hydrophilic polymer in the dense layer of the inner surface of a hollow fiber membrane is adjusted within a specified range, and the mass ratio of the hydrophilic polymer in the dense layer of the inner surface of the membrane is at least 1.1 times larger than the mass ratio of the hydrophilic polymer in the outer surface of the membrane. In particular, this method is based on a technical idea to increase the mass ratio of the hydrophilic polymer in the dense layer of the inner surface of the membrane to thereby improve the compatibility thereof with blood, and to decrease the mass ratio of the hydrophilic polymer in the outer surface of the membrane to thereby suppress the sticking of the hollow fiber membranes which would occur when drying the membranes. This technique also solves another problem: i.e., the invasion of endotoxin in a dialyzate into the blood side is inhibited. However, there still remains unsolved the problem that the priming of the membrane tends to lower because of too low a mass ratio of the hydrophilic polymer in the outer surface of the membrane. It is therefore needed to solve this problem.
There is disclosed another method of solving the problem of the invasion of endotoxin in a dialyzate into the blood side (cf. JP-A-2001-38170). In this method, the contents of hydrophilic polymers in the proximate layers of the inner surface and the outer surface, and the intermediate layer of a hollow fiber membrane having an uniform membrane structure, determined by infrared-absorbing analysis method, are specified so as to suppress the invasion of endotoxin into the blood side. However, also, this method can not solve the problem of lower priming of the membrane, as well as the former method. In addition, there is a further problem in that the larger size pores of the outer surface of the hollow fiber membrane lower the pressure resistance of the membrane. Therefore, such a membrane has a danger of bursting when used for hemodiafiltration or the like in which the pressure of a fluid is higher than that in the conventional therapies.
There are further disclosed methods for improving the compatibility of membranes with blood and for reducing the amount of hydrophilic polymers eluted into blood, by specifying the contents of the hydrophilic polymers in the inner surfaces of hollow fiber membranes (cf. JP-A-6-296686, JP-A-11-309355 and JP-A-2000-157852).
However, any of the above patent literature does not teach the ratio of the hydrophilic polymer present in the outer surface of the hollow fiber membrane, i.e., the reverse side of the blood-contacting side of the hollow fiber membrane, and thus, any of the inventions of the above publications is not able to improve all the problems attributed to the ratio of the hydrophilic polymer present in the outer surface of the hollow fiber membrane.
There is disclosed a method of solving the problem of the invasion of endotoxin into the blood side, out of the foregoing problems (cf. JP-A-2000-254222). This method is devised by taking advantage of the properties of endotoxin which has a hydrophobic moiety in the molecule and which is apt to be adsorbed onto a hydrophobic material. Specifically, in this method, the ratio of a hydrophilic polymer to a hydrophobic polymer in the outer surface of a hollow fiber membrane is adjusted to 5 to 25%. Surely, this method is effective to suppress the invasion of endotoxin into the side of blood. However, it is needed to remove the hydrophilic polymer in the outer surface of the membrane by washing, so as to impart this feature to the membrane. Accordingly, long treating time is required for this washing, which is disadvantageous in cost. For example, in an Example of the invention of the above patent publication, a hollow fiber membrane is washed by showering with hot water of 60° C. for one hour and washed with hot water of 110° C. for one hour.
This method of decreasing the amount of the hydrophilic polymer in the outer surface of the membrane is effective to inhibit the invasion of endotoxin into the side of blood. However, the hydrophilicity of the outer surface of the membrane becomes lower, which causes the following disadvantage: when a bundle of hollow fiber membranes dried after incorporated into a module is again wetted and incorporated into a module, the hollow fiber membranes become poor in compatibility with physiological saline for wetting the membranes. Undesirably, this method may induce poor priming, i.e., insufficient purging the membranes of an air during a membrane-wetting step. For example, there are disclosed methods of improving this problem, in which a hydrophilic compound such as glyceline or the like is blended (cf. JP-A-2001-190934 and Japanese Patent No. 3193262). These methods, however, have problems in that the hydrophilic compound behaves as a foreign matter during dialysis and also tends to deteriorate by light or the like, which gives an adverse influence on the storage stability of a module, and also in that the hydrophilic compound hinders an adhesive from bonding for fixing a bundle of hollow fiber membranes in a module when the membranes are incorporated into the module.
There are disclosed methods of avoiding the sticking of hollow fiber membranes, i.e., another problem out of the foregoing problems: in any of these methods, the rate of pore area of the outer surface of a membrane is adjusted to 25% or more (cf. JP-A-2001-38170 and JP-A-7-289863). While these methods are surely effective to avoid the sticking of the hollow fiber membranes, the strength of the membranes becomes lower due to the higher rate of pore area, which may lead to the leakage of blood or the like.
Further, a method by specifying the rate of pore area and the pore area of the outer surface of a membrane is disclosed (cf. JP-A-2000-140589)